1. Field of the Invention
The present invention relates to methods for producing nanometer particles of compounds that are useful in pharmaceutical, food and cosmetic applications. Specifically, this invention is concerned with producing nanometer particles by utilizing a technique in which a solution of non-aqueous or mixed aqueous/non-aqueous solvent and a solute which is compound that is poorly soluble or substantially insoluble in water is finely sprayed and dried into a fluidized bed of one or more carrier excipients.
2. Related Art
Particles of compounds having low water-solubility are commonly used in a wide variety of applications, including ceramics, paints, inks, dyes, lubricants, pharmaceuticals, food products, pesticides, insecticides, fungicides, fertilizers, chromatography columns, cosmetics, lotions, ointments, and detergents. Aqueous dispersions of particles are used in many cases to avoid hazards such as flammability and toxicity associated with organic solvents. Such dispersions typically have a broad range of particle size.
In many cases product performance can be improved by controlling the particle size distribution. In general, smaller particles of a compound will dissolve faster than larger particles of the same compounds. Control of particle size is, therefore, important in controlling the rate of solubilization.
Obtaining particle sizes in the nanometer range is often useful for enhancing the effectiveness of compounds. This is particularly true for compounds that are practically insoluble or slightly soluble in water. Nanometer particles provide a large specific surface area, leading to increased dissolution rate and bioavailability of pharmaceutical drug substance, digestibility of food ingredients, as well as functional effectiveness of cosmetic ingredients. In particular, reducing the particle size of practically insoluble or poorly-soluble drug substances has been shown to increase the dissolution rate and consequently, their bioavailability.
A limited number of methods are known in the art for producing materials having nanometer particle sizes.
G. G. Liversidge et al., U.S. Pat. No. 5,145,684 issued on Sep. 8, 1992 describes a method for forming nanoparticles of a water-insoluble drug by wet milling in the presence of a surfactant. Wet bead milling, in which the material, suspended in aqueous medium, is milled by using glass, polymer, aluminum, zirconium or other metal beads. The milling process can be performed in a roller mill, vibratory mill or high energy mechanical mill. A dispersion consisting of a liquid dispersion medium and the above-described particles is described as being stable.
H. W. Bosch et al., “Process for Preparing Therapeutic Compositions Containing Nanoparticles,” U.S. Pat. No. 5,510,118 issued on Apr. 23, 1996 describes a method for forming nanoparticles of a drug by high pressure homogenization. In this method, a suspension of the material is forced to pass through a narrow orifice by applying a high pressure. The high shear applied to the suspension reduces the particle size of the suspension.
V. Krukonis, “Supercritical Fluid Nucleation of Difficult-to-Comminute Solids,” presented at the American Institute of Chemical Engineers, San Francisco, Nov. 25–30,1984, describes a method for forming nanoparticles of a drug using super-critical fluid technology. A solution of material in liquid carbon dioxide or in a mixture with another solvent is precipitated by reducing the applied pressure at a controlled rate to form particles of solid compound that have a nanometer size range.
With respect to wet bead milling, the batch size for roller or vibratory mills is limited by the size of the container on the mill. High energy mechanical milling is a continuous process capable of achieving nanometer particles in a short period of time. However, the beads are subjected to severe collisions with the metal chamber, such that abrasion could result in glass or metal contamination of the milled material.
The high pressure homogenization method described by Bosch et al. is usually used to reduce the size of liquid globules in dispersed systems, i.e., emulsions or liposomes. The success of high pressure homogenization method for solid materials is dependent on the physical property of the materials.
Super-critical fluid technology has at present a limitation in batch size. The feasibility of producing nanometer particles on a commercial scale has not yet been proven.
Iwasaki et al., U.S. Pat. No. 4,851,421 discloses biocidal fine powders containing particles with a diameter of 0.5 micron or less that are formed by wet milling a dispersion liquid of a biocidal substance with a rigid media having a particle diameter of 0.5 mm or less. Biocidal substances include germicides, herbicides, insecticides, miticides and tickicides that are water-insoluble. Iwasaki et al. also disclose that the resulting biocidal fine powder can more promptly permeate through the surfaces of plants as well into insect bodies and microbe cells.
European application EP 0 411629, published Feb. 6, 1991, describes a process whereby ultrafine particles of a slightly-soluble drug, whose average diameter is less than 2 to 3 μm, are obtained by milling the drug in the presence of a grinding aid selected from a sugar and a sugar alcohol. The weight ratio of said sugar or sugar alcohol is 2.5 to 50 parts by weight to one part of the drug, and the micronized drug has an average diameter of less than 1 μm.
A need continues to exist in the art for a method of producing nanometer particles of compounds, which method can conveniently be scaled up to production scale, and does not contaminate the final product with metals or glass.